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Objectives

Basics of electrophysiology. Objectives. 1. Know the meaning of Ohm’s Law. 2. Know the meaning of ionic current. 3. Know the basic electrophysiology terms. 4. Know the effects of changing membrane potential in excitable cells.

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Objectives

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  1. Basics of electrophysiology Objectives 1. Know the meaning of Ohm’s Law 2. Know the meaning of ionic current 3. Know the basic electrophysiology terms 4. Know the effects of changing membrane potential in excitable cells 5. Know the effects of changing ionic conductances in excitable cells 6. Understand the terms ‘activation’ and ‘inactivation’

  2. What do the following categories of drugs have in common? antiarrhythmics anxiolytics antihypertensives anticonvulsants sedatives/hypnotics antidiabetics anesthetics They all include drugs that act on ion channels

  3. Therefore... Ion channels are interesting to pharmacists

  4. Channel selectivity Na+ K+ Ca2+ molecules Cl-

  5. Channel gating Voltage Extracellular ligand Intracellular ligand

  6. Ligand-gated ion channels (Dr. Ishmael) Voltage-gated ion channels

  7. Voltage-gated ion channels • Voltage sensor • Inactivation • Voltage-dependent block

  8. Voltage sensor

  9. Inactivation extracellular + - intracellular

  10. Voltage-dependent block + extracellular + - intracellular +

  11. A guide to “Electrophysiologese” Membrane potential (Em): The voltage difference across the cell membrane (inside vs outside) (millivolts) Resting potential: The membrane potential at which the membrane spends most of its time Action potential: The transient change in membrane potential due to active properties of the membrane Electrotonic potential: A change in membrane potential due to passive properties of the membrane

  12. A guide to “Electrophysiologese” Depolarization: A change of membrane potential in the positive direction. Repolarization: Return of the membrane potential to the resting potential after a depolarization. Hyperpolarization: A change of membrane potential to a more negative value than the normal resting potential.

  13. A guide to “Electrophysiologese” Inward current: Net movement of positive ions into the cell, or net movement of negative ions out of the cell. By convention, plotted as negative current. Inward current causes depolarization Outward current: Net movement of positive ions out of the cell, or net movement of negative ions into the cell. By convention, plotted as positive current. Outward current causes repolarization/hyperpolarization

  14. A guide to “Electrophysiologese” Excitable cell: A cell that can fire action potentials Excitability: The ability to fire action potentials Threshold potential: The membrane potential at which an action potential fires

  15. Excitable cells fire action potentials mV 2 msec

  16. A nerve cell (neuron) axon Cell body

  17. Hodgkin and Huxley Voltage clamp

  18. Depolarization changes the conductance of the membrane

  19. Inward current is carried by Na+ ions Outward current is carried by K+ ions

  20. Hodgkin & Huxley reconstructed the action potential

  21. Electrochemical gradients Ion channels allow ions to pass through Why would ions want to pass through? Which way will they go? At what rate will they go through?

  22. Concentration gradient (chemical gradient) Net flow

  23. + - Membrane potential (electrical gradient) Anion channel Cation channel + -

  24. - + Membrane potential (electrical gradient) Anion channel Cation channel + -

  25. + + + + + + + + + + + + + + + + + + + + + + Electrochemical gradient - - - - - - - - - - - - - - - - - - - + - - - -

  26. ( ) (At physiological temperature) . [Xo] 60 EX = log zX [Xi] [Xi] = Ionic concentration inside the cell [Xo] = Ionic concentration outside the cell zX = ionic valence (number and sign (+ or -) of charges on ion) EX is in millivolts (mV) [Xo] and [Xi] are in millimolar (mM) The Nernst potential

  27. Extracellular concentration (mM) Intracellular concentration (mM) Nernst potential (mV) ion Na+ 145 12 67 K+ 4 155 -98 Ca2+ 1.5 0.0001 129 Cl- 123 4.2 -90 If Cl- is passively distributed (not pumped), ECl = resting potential

  28. The different concentrations of physiological ions means that they have different Nernst potentials. Therefore, at any membrane potential, there is a driving force on at least some of the ions. (driving force = membrane potential – Nernst potential) At physiological membrane potentials, the driving force is inward for Na+ and Ca2+ ions and outward for K+ ions. Therefore, at physiological membrane potentials, there are inward Na+ and Ca2+ currents and outward K+ currents.

  29. Ohm’s law: V=IR; I=GV V or E = potential (Volts); I = current (Amps); R = resistance (Ohms); G = 1/R = conductance (Siemens) The cell membrane is a resistor

  30. Ohm’s Law High G I I=GV Low G V Slope = conductance (G)

  31. Ohm’s Law I IK=G(Em-EK) EK = -98 mV V ENa = 67 mV INa=G(Em-ENa)

  32. At rest, ionic gradients are maintained by the Na+-K+ ATPase INa 2 K+ + + + + + + + + + ATPase - - - - - - - - - - ICl IK 3 Na+

  33. membrane potential = -90 mV GNa is low GK is high INa outside + + + + + + + + + - - - - - - - - - - inside ICl IK If the membrane potential is not changing, -INa = -((-90mV)-ENa) x GNa = (IK) = ((-90mV)-EK) x GK ECl = -90 mV (Ca2+ channels not shown)

  34. Na+ channels just opened GNa is very high membrane is depolarizing GK is high INa outside + + + + + - - - - - inside ICl IK (no significant effect on concentration) INa > -(IK)

  35. membrane potential = +30 mV GNa is very high GK is high ICl INa - - - - - outside + + + + + inside IK (outward current, inward Cl flow) INa = (30mV-ENa) x GNa = -(IK + ICl) = -[(30mV-EK) x GK + (30mV-ECl) x GCl ]

  36. membrane potential = -90 mV ECl = -90 mV INa outside + + + + + + + + + - - - - - - - - - - inside ICl IK What will happen to the membrane potential if we open more Cl- channels? What will happen to excitability if we open more Cl- channels?

  37. chord conductance equation

  38. [Na+]i, [K+]i, [Cl-]i don’t change significantly. Depolarization opens Ca2+ channels. [Ca2+]i increases. Ca2+ Action potential Postsynaptic cell axon Neurotransmitter receptor Electrical signaling changes intracellular Ca2+

  39. Here are the main points again: Nerves, muscles and other excitable cells use electrical signaling Physiologically, Na+ channels always pass inward current; K+ channels always pass outward current. Inward current depolarizes the membrane. Outward current repolarizes/hyperpolarizes the membrane. In an excitable cell, depolarization causes activation of Na+ channels, followed by inactivation of Na+ channels and activation of K+ channels. These processes underlie the action potential of the nerve axon.

  40. Net movement of ions through channels is always down the electrochemical gradient. Concentration gradients are maintained by ATPases and ion exchangers The membrane potential depends on the relative conductance of the membrane for K+, Na+, Cl- and Ca2+ ions. Ion selectivity varies among ion channels. In cells that don’t actively transport Cl-, opening Cl- channels decreases excitability by stabilizing the membrane potential. The intracellular response to electrical signaling is a change in cytoplasmic Ca2+.

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